What impact could the microbiome have on CAR-T therapy? – an interview with M. Bilal Abid

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This image shows Bilal Abid.Chimeric antigen receptor (CAR) T-cell therapy is a highly complex and innovative treatment that involves collecting and using the patients’ own immune cells to treat their cancers. In this interview we speak to M. Bilal Abid from the Medical College of Wisconsin (WI, USA) about what impact the gut microbiome could have on this immune-engaging therapy, and the regulations currently surrounding the use of probiotics.

First, could you just introduce yourself and tell us a bit about your background?

So, I am an Assistant Professor of Medicine jointly with the divisions of Hematology/Oncology and Infectious Diseases at the Medical College of Wisconsin, Milwaukee. I attended medical school at the Aga Khan University (Karachi, Pakistan) and I then received clinical and research training at Penn State University (PA, USA), the National University of Singapore (Singapore), University of Bristol Cancer Institute (UK), and lastly, at the Medical College of Wisconsin.

My clinical practice is mainly focused on transplantation ID and hematology. My clinical and translational research interests include stem cell transplantation, immunotherapy, CAR T-cells and transplant-related infectious diseases. I am currently involved in research studies and clinical trials related to infections that complicate bone marrow transplantation and cellular therapy.

And could you introduce the work you are currently doing on the role of the gut microbiome in immune-engaging therapy?

In a collaborative study at the Medical College, involving clinicians and basic scientists from several disciplines, we are currently analyzing potential impact of gut microbiota on the response to CAR T-cells and the survival of those patients receiving this therapy.

We are collecting stool samples and correlative data at defined treatment timepoints to study the outcomes of patients with hematological malignancies who go on to receive CAR T-cells. We are looking at the diversity and composition of the gut microbiome by performing taxonomic profiling, using 16S ribosomal RNA sequencing and metagenomic whole-genome shotgun sequencing in patients’ stool samples. Concurrently, blood samples and tumor biopsies are being collected at matched treatment timepoints, when possible, to assess for genomic alterations, as well as density and phenotype of tumor-infiltrating and circulating immune cells.

We have hypothesized that patients who respond to CAR T-cells have a higher gut microbial diversity in comparison to non-responders. And their gut microbiota is enriched in in taxa belonging to Firmicutes and Verrucomicrobia phyla.

How did you come up with this idea of using the gut microbiome with CAR T-cells?

I first thought of it in January 2018 and this was perhaps a natural occurrence as the idea really marries my background in two distinctive but overlapping specialties – hematology/oncology and infectious diseases.

At each stage of my career, I had engaged in projects that had taught me lab-based and translational skills alongside my clinical training. I learned pathological and immunological skillset at the Agha Khan University. Then, during residency at Penn State, I worked in the lab of a cancer scientist on two preclinical studies, an opportunity that helped me learn about the basics of preclinical studies, handling mice models, generation of patient-derived xenografts and how we can translate basic science data into clinically meaningful information for further studies.

Following that, working on manufacturing CAR T-cells in a commercial lab setting introduced me to the mechanistic and structural intricacies involved with newer generations of CAR T-cells. I learned how a chimera is used to target specific antigen expressed only on cancer cells, and other skills related to commercial manufacturing of CAR T-cells.

Having had clinical and research training in these subspecialties and bench research experience with CAR T-cells, my inclination towards understanding how the gut microbiome could impact CAR-T therapy was natural. Over the last 3–5 years, growing evidence has implicated a clear role of the gut microbiome in enhancing responses to immunotherapy. In parallel, my interest grew in this area as the field transitioned from murine models to clinical studies, and I extrapolated the immunological crosstalk that occurs between the gut microbes and the immune system to CAR T-cells.

And do you think that manipulation of the microbiome could be used to treat certain disease states?

Yes! For me, the future of health and wellbeing lies in a healthy gut microbiota. It is amazing to see the impact of gut microbiota on even those disease states that were not historically linked to the immune system – for example, neurological and cardiovascular disease – in comparison to those that are linked to the immune system, such as infections, autoimmune diseases and cancer.

The challenges in this field are related to the fact that the field is still in its infancy. Specifically, whether the disease state leads to dysbiosis or dysbiosis leads to the disease state, quality control, research standards and issues related to proof-of-concepts. We really need to have proof-of-concept in order to be certain about mechanistics and causality. Additional challenges include lack of a universally acceptable definition of a healthy gut microbiome and, honestly, we may never be able to achieve that. The variability and heterogeneity within and across communities and lifetimes are some of the aspects that we really need to embrace as the field progresses in the era of precision medicine.

And what could be some of the ways we could manipulate and modulate the microbiome?

In general, the gut taxa could be modified in certain ways. For example, patients can be randomized to receive dietary interventions that could include a non-Western diet (or high-fiber, low-carb, ketogenic diet) or non-absorbable oligosaccharides contained in potato starch, which would allow blossoming of ‘good’ taxa. In addition, it could be modified via the administration of prebiotics or probiotics, or the administration of narrow-spectrum antibiotics specifically targeting and depleting unfavorable taxa – once they have been clearly defined. We could also do fecal microbiota transplant from healthy donors, although, some of recent studies have indicated the need for more strict screening protocols for this procedure.

Specific to advanced immune-engaging therapies such as CAR-T, TRUCKs, adoptive cell therapy, tumor infiltrating lymphocyte infusions etc., there are several mechanisms by which the microbiome could be modulated. First, the gut microbiome has tumor-suppressive function via a variety of proteins and metabolites. It is known that the gut microbiota can impact effector T-cells, and CAR T-cells are essentially engineered T cells. Hence, the gut taxa could impact CAR T-cells in a manner similar to the way they would impact endogenous T-cells.

Another mechanism could be that we could modulate the gut microbiome by impacting conditioning before CAR T-cell administration. Any definitive therapy that we do in hematology/oncology, we condition our patients to lymphodeplete prior to therapy. So, for instance, cyclophosphamide (CYC) is a commonly used chemotherapeutic agent for conditioning purposes. Part of its therapeutic effect is through the induction of antitumor responses. It became known that CYC alters the composition of gut taxa to stimulate Th17 production which in turn renders the tumor susceptible to CYC.

Third, we could modulate the microbiome by upregulation of IL-6/STAT3 signature. Fraietta et al. proposed a model to predict response to CD19+ CAR T-cells in heavily pre-treated, high-risk CLL patients based on baseline T-cell qualities. They showed an association between the upregulation of the IL-6/STAT3 signature and durable clinical remissions in CLL patients treated with CD19+ CAR T-cells. It remains unknown if the gut microbiota could have any impact on the intrinsic transcriptome profile of a CAR-T cell but IL-6/STAT3 signature could be regulated via defined gut microbiota, for instance, at the time of CAR T-cell infusion.

Finally, after ‘favorable’ and ‘unfavorable’ taxa become known in this setting, we could potentially use narrow-spectrum antibiotics to deplete select, detrimental gut microbes. A few studies have already demonstrated this potential in a preclinical setting.

You mention probiotics to manipulate the microbiome, what are some of the challenges surrounding the use of probiotics?

There are several. The biggest one to me is that the evidence is mixed. In parallel to the trials that showed efficacy of probiotics, there has been nearly equivalent number of trials that showed a lack of efficacy (PLACIDE) and some even suggesting harm (PROPATRIA). For example, one multicenter double-blind placebo-controlled trial that involved a multi-strain preparation of Lactobacilli bifidobacterium was shown to be effective in the prevention of antibiotic-associated diarrhea as well as C. diff infections; however, another randomized, controlled trial performed in the UK showed that probiotics, again including a preparation of Lactobacillus Bifidobacterium, were ineffective in reducing the severity of C. diff infections.

Other challenges include the quality of the existing data. A large majority of probiotics data stem from meta-analyses and underpowered randomized controlled trials and the information, both for and against commercial probiotics, should be interpreted considering the discrepancies between the results of these two types of study methods. Additionally, studies have shown that probiotics may not get colonized homogeneously. It is contingent upon one’s baseline gut taxa – the indigenous microbiota – if the probiotic would colonize the gut or gets rejected – the concept of ‘persistor’ and ‘resistor’.

Another challenge is the lack of a universally acceptable definition – studies addressing benefit or harm associated with probiotics use suffer from the fact that ‘probiotics’ is an ill-defined term, making any scientifically rigorous judgment virtually impossible. Furthermore, most current probiotics are marketed as nutritional supplements with ‘Generally Recognized as Safe’ (GRAS) status under the US FDA and cannot be marketed with a drug claim. None have been studied in a way similar to a drug that is brought to market: a quality-controlled product of verified potency, given at a specified dose, at a specific point in time of a disease or condition progression, for a specified time, to achieve a specific outcome. Hence, probiotics may not be truly ‘GRAS’ and there are currently insufficient data for physicians to be recommending probiotics indiscriminately.

Off the back of some of these challenges, what are the current guidelines around probiotics, and how do you think those should potentially be modified?

So, currently, the majority of medical professional societies endorse the use of probiotics in one way or another. For instance, the IDSA clinical practice guidelines for the management of infectious diarrhea that were published in 2017 tacitly endorses the use of probiotics, though deferred to other guidelines for specific probiotics. In the wake of this growing body of evidence of the potentially ‘harmful’ impact of commercial probiotics, physicians’ and professional bodies’ endorsements of their illness-directed consumption and rampant general usage would, perhaps, be best avoided. A ‘one size fits all’ prescription strategy should be discouraged until a more universally acceptable ‘favorable taxa’ or a ‘personalized probiotic’, to complement an individual’s native microbiota, gets fashioned. Large, placebo-controlled, multicenter trials with concomitant accrual of microbiome data before and after intervention are needed before a more rationally-designed bacterial consortium becomes available.

This might come across as a very strong statement, but I just want to say that probiotic use should be limited to indications only pertaining to specific themes, whereby randomized control trials have already shown therapeutic efficacy, such as in the case of antibiotic-associated diarrhea, C. diff infection, irritable bowel syndrome, inflammatory bowel disease and reduction of risk for neonatal sepsis and necrotizing enterocolitis. The other point that I would make is probiotics may potentially be harmful to the critically ill and the immunocompromised patients and are best avoided in cancer patients undergoing active treatment.

Finally, where do you hope the field will be in the next 5–10 years?

I think this is an evolving and a very exciting field, and with time will bloom to its full potential. In the future, we will know more about the gut microbiome and advanced immune-engaging therapy, a field I call “onco-microbiome.” It will be stronger, better regulated, and will have a larger and safer bandwidth of interventional and therapeutic options, moving forward. As I recently wrote in an article for Journal for ImmunoTherapy of Cancer: “The field of onco-microbiome is evolving. Driven by the era of precision oncology, it is likely to draw greater interest and funding. The impact of gut microbiome on immune-based cancer therapy will be a breakthrough in terms of improving patient’s outcomes and the field is certainly ripe to live up to its hype.”

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